Alcoholism is a substantial medical and social problem in the U.S. and relapse represents a major challenge to treatment efforts. Currently, there is no therapeutic intervention that is fully satisfactory in preventing relapse and sustaining abstinence. While dependence is known to contribute to the problem of relapse, this issue has not been thoroughly studied. The focus and overall objective of this proposal is to utilize a mouse model of EtOH dependence and relapse to evaluate the ability of pharmacotherapies to reduce voluntary EtOH drinking, as well as neurochemical alterations that may underlie motivation to drink in dependent compared to non-dependent animals. A contemporary view of alcohol and drug addiction indicates that activation of different neurochemical systems within the brain reward ("motive") circuitry play a critical role in establishing the initial reinforcing effects of EtOH, as well as shaping motivational forces that perpetuate EtOH use/abuse during later stages in addiction. The mesolimbic dopamine pathway, with the nucleus accumbens being a key target structure, is a prominent component of this circuitry. Among several neurotransmitter systems that impinge on this dopamine pathway, glutamate transmission has emerged as a key player in contributing to the motivational effects of EtOH. A guiding principle of this proposal is that activation of the mesolimbic dopamine pathway plays an important role in establishing the acute reinforcing properties of EtOH, while adaptive changes in dopamine and glutamate transmission contribute to conditions that promote relapse and engender excessive EtOH drinking behavior characteristic of dependence. The research plan entails use of in vivo microdialysis procedures to characterize changes in extracellular levels of dopamine and glutamate in nucleus accumbens associated with voluntary EtOH drinking, as well as evaluation of various pharmacological agents for their ability to influence concomitant measures of behavior (drinking) and associated neurochemical changes in the model of dependence and relapse. The overall goal of the proposal is to provide new information about neural substrates underlying EtOH drinking in dependent compared to nondependent subjects, as well as evaluate the ability of potential pharmacotherapeutics to impact both neurochemical and behavioral (drinking) changes related to dependence and relapse.